1. Field of the Invention
The present invention relates to a critical epitope of human cytochrome P4502E1 (CYP2E1) associated with the development of hepatic autoimmune disease.
2. Background Information
Cytochrome P450 2E1 (CYP2E1) is a 493 amino acid enzyme (SEQ ID NO:1) involved in the monooxygenation of drugs and other xenobiotic agents. (1). CYP2E1 is a highly conserved protein in humans, and CYP2E1 is a known target of autoantibodies in several hepatic autoimmune diseases. (2). For example, autoantibodies to CYP2E1 have been identified in persons with drug induced liver injury (DILI). (2). DILI accounts for approximately 13% of acute liver failure in the United States and is the third most common cause of acute liver failure. (3). A type of DILI develops in susceptible individuals following administration of halogenated volatile anesthetics. (2, 3). Under physiological conditions, oxidative metabolism of the anesthetic produces trifluoroacetylchloride (TFA), which is a reactive metabolite that can covalently bind to and alter native liver proteins. (2, 3). The TFA-protein complexes, known as drug haptens, are novel autoantigens or hapten-autoantigen complexes (neoantigens) capable of eliciting allergic or autoimmune responses. (2, 3).
A second type of DILI is alcohol-induced liver disease. (2). Individuals chronically exposed to alcohol also develop autoantibodies to CYP2E1. (2).
Chronic viral infections are also known to induce autoimmunity directed to CYP2E1. (2). For example, chronic infection with hepatitis C virus (HCV) is known to induce autoimmune reactions. (2). Individuals with chronic hepatitis C (CHC) express decreased levels of CYP2E1, as measured by mRNA copy number (4), and CYP2E1 autoantibodies have been demonstrated in CHC patients (5). Indeed, a previous study has shown that CYP2E1 autoantibody levels correlate with the severity of necroinflammation in CHC patients after liver transplantation. (6). Thus, CYP2E1 plays a role in hepatic autoimmune disorders and there is a need to elucidate the mechanism of disease, including the formation of CYP2E1 autoantibodies.